AIMS: The credibility of bioelectromagnetic effects requires both convincing experiments and theoretical understanding of interaction mechanisms and thresholds. Here we propose theoretical modelling of basic interaction mechanisms, biological background and noise. We will emphasize cellular subsystems that can be reasonably modelled, and will seek: (1) identification of the key parameters, (e.g., cell aggregate size, enzyme kinetics, membrane electrical permittivity, epsilon(m)), (2) dependence of an interaction on the parameters (e.g., transmembrane flux proportional to E2(e)), (3) noise or fluctuation levels for the parameters, (e.g., 1/f noise in the transmembrane voltage), (4) the magnitude, frequency spectrum and fluctuations in biological background fields (e.g., an EGC field at a distant tissue site), and (5) threshold conditions for an interaction to occur (e.g., use of a combined signal-to-(background + noise) ratio with a particular interaction mechanism). SIGNIFICANCE: The possibility of "weak" electromagnetic field biological effects has generated considerable controversy because of apparent violations of basic physical laws. Both biologically generated fields in tissue ("biological background") and fundamental physical fluctuations ("noise") have been cited as precluding "weak" biological effects. Thus, basic questions relating to "detection" of electromagnetic fields by biological systems must be directly confronted. In this context, "detection" is used to indicate that a response is really due to an external electromagnetic field (e.g., 50 and 60 Hz environmental fields), and is not overwhelmed by a combination of background and noise. Further, in order to alter cell function, the physical detection process must lead to altered biochemistry. Unless such detection can be understood in the context of background, noise and mechanism, alleged effects, or their absence, will not be credible. PRIOR 7 PRELIMINARY WORK: We have developed theoretical models for (1) the thermal noise limit for the response of cells to an electric field, (2) electroconformational coupling of membrane enzymes, (3) electroporation- related phenomena, and have preliminary results for (4) a model for altered molecular protrusion, and (5) the threshold for a magnetic interaction for soluble intracellular molecules. METHODS: We will treat cellular subsystems which can be plausibly represented by a physical model, and which provide a possible coupling to one or more biochemical pathways. Modeling of interactions with external electromagnetic fields will be developed, with an emphasis on predicting the dependence on key parameters. Our primary hypothesis involves electroconformation changes of membrane entities (membrane macromolecules, the membrane itself, and membrane/macromolecule complexes). Our secondary hypothesis involves soluble intracellular molecules (e.g., DNA), and possible intracellular magnetic interactions through induced electric fields. Biological background fields and intrinsic noise will be combined with theoretical models to estimate thresholds for bioelectromagnetic effects.